1eas
From Proteopedia
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| - | [[Image:1eas.gif|left|200px]] | + | [[Image:1eas.gif|left|200px]] |
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| - | '''NONPEPTIDIC INHIBITORS OF HUMAN LEUKOCYTE ELASTASE. 3. DESIGN, SYNTHESIS, X-RAY CRYSTALLOGRAPHIC ANALYSIS, AND STRUCTURE-ACTIVITY RELATIONSHIPS FOR A SERIES OF ORALLY ACTIVE 3-AMINO-6-PHENYLPYRIDIN-2-ONE TRIFLUOROMETHYL KETONES''' | + | {{Structure |
| + | |PDB= 1eas |SIZE=350|CAPTION= <scene name='initialview01'>1eas</scene>, resolution 1.8Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene> and <scene name='pdbligand=TFK:3-[[(METHYLAMINO)SULFONYL]AMINO]-2-OXO-6-PHENYL-N-[3,3,3-TRIFLUORO-1-(1-METHYLETHYL)-2-OXOPHENYL]-1(2H)-PYRIDINE ACETAMIDE'>TFK</scene> | ||
| + | |ACTIVITY= [http://en.wikipedia.org/wiki/Pancreatic_elastase Pancreatic elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.36 3.4.21.36] | ||
| + | |GENE= | ||
| + | }} | ||
| + | |||
| + | '''NONPEPTIDIC INHIBITORS OF HUMAN LEUKOCYTE ELASTASE. 3. DESIGN, SYNTHESIS, X-RAY CRYSTALLOGRAPHIC ANALYSIS, AND STRUCTURE-ACTIVITY RELATIONSHIPS FOR A SERIES OF ORALLY ACTIVE 3-AMINO-6-PHENYLPYRIDIN-2-ONE TRIFLUOROMETHYL KETONES''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1EAS is a [ | + | 1EAS is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EAS OCA]. |
==Reference== | ==Reference== | ||
| - | Nonpeptidic inhibitors of human leukocyte elastase. 3. Design, synthesis, X-ray crystallographic analysis, and structure-activity relationships for a series of orally active 3-amino-6-phenylpyridin-2-one trifluoromethyl ketones., Bernstein PR, Andisik D, Bradley PK, Bryant CB, Ceccarelli C, Damewood JR Jr, Earley R, Edwards PD, Feeney S, Gomes BC, et al., J Med Chem. 1994 Sep 30;37(20):3313-26. PMID:[http:// | + | Nonpeptidic inhibitors of human leukocyte elastase. 3. Design, synthesis, X-ray crystallographic analysis, and structure-activity relationships for a series of orally active 3-amino-6-phenylpyridin-2-one trifluoromethyl ketones., Bernstein PR, Andisik D, Bradley PK, Bryant CB, Ceccarelli C, Damewood JR Jr, Earley R, Edwards PD, Feeney S, Gomes BC, et al., J Med Chem. 1994 Sep 30;37(20):3313-26. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/7932559 7932559] |
[[Category: Pancreatic elastase]] | [[Category: Pancreatic elastase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: hydrolase (serine protease)]] | [[Category: hydrolase (serine protease)]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 10:52:46 2008'' |
Revision as of 08:52, 20 March 2008
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| , resolution 1.8Å | |||||||
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| Ligands: | , and | ||||||
| Activity: | Pancreatic elastase, with EC number 3.4.21.36 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
NONPEPTIDIC INHIBITORS OF HUMAN LEUKOCYTE ELASTASE. 3. DESIGN, SYNTHESIS, X-RAY CRYSTALLOGRAPHIC ANALYSIS, AND STRUCTURE-ACTIVITY RELATIONSHIPS FOR A SERIES OF ORALLY ACTIVE 3-AMINO-6-PHENYLPYRIDIN-2-ONE TRIFLUOROMETHYL KETONES
Overview
A series of nonpeptidic inhibitors of human leukocyte elastase (HLE) is reported. These trifluoromethyl ketone-based inhibitors contain a 3-amino-6-phenylpyridone group as a central template. The effect of varying the N-3 substituent in these inhibitors on in vitro potency, physical properties, and oral activity in a hamster based, HLE-induced lung damage model is described. The variety of substituents at this position that have little effect on in vitro potency supports the idea that this region of the molecule does not interact strongly with the enzyme. One exception to this generality is 13k, which is substituted with a (4-acetamidophenyl)sulfonyl group. This compound has a K(i) of 0.7 nM and is, in vitro, the most potent inhibitor in the series. In contrast, variation of the N-3 substituent was found to have a dramatic effect on activity after oral administration. Several analogs, including the parent amine, 7, formamide, 2u, benzyl sulfamide, 13e, and benzyl sulfonamide, 13f, show significant activity when administered at an oral dose of 2.5 mg/kg. Support for the modeling-based design concepts was obtained through in vitro SAR results and X-ray crystallographic analysis of the complex between 13d and porcine pancreatic elastase (PPE), a closely related enzyme.
About this Structure
1EAS is a Single protein structure of sequence from Sus scrofa. Full crystallographic information is available from OCA.
Reference
Nonpeptidic inhibitors of human leukocyte elastase. 3. Design, synthesis, X-ray crystallographic analysis, and structure-activity relationships for a series of orally active 3-amino-6-phenylpyridin-2-one trifluoromethyl ketones., Bernstein PR, Andisik D, Bradley PK, Bryant CB, Ceccarelli C, Damewood JR Jr, Earley R, Edwards PD, Feeney S, Gomes BC, et al., J Med Chem. 1994 Sep 30;37(20):3313-26. PMID:7932559
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